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Targeted

By Sheila Hunter,2014-07-19 00:48
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TargetedTarget

    Targeted

血栓与止血学2004年第1鲞笠塑

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    ;述评?(Commentaries)

    ;TargetedThrombolyticTherapy

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    ;99?

    ;HUYu胡豫

    ;KeywordsThroml~lytictherapy;Drugta~g;Antibody?mediatedthrombolysis;Catheter-directedad

    ministration;Nanoparticle-

    ;targetedfibrinolysis

    ;[CLCnumber]R453[Documentcede]C[ArticleID]1009.6213(2004)03.0O99.02

    ;Venousandarterialthrombosisarecloselyrelatedto ;manyseverediseases,especiallytocardiovascularandceFe? ;brovasulardisorders.Thrombol~ictherapyhasbeenproven ;tobeaneffectivemethodtotreatsuchdisease,whichde

    ;creasedthemortalityandmorbiditygready.However,even ;underthemostrecenttreatmentregime,hemorrhagiccon? ;plicationsandearlyreocclusionaremajorlimitationsofcur? ;rentthrombolytictherapy.Therefore,therecontinuestobe ;interestindevelopinginorepotentandspecificthrombolytic ;therapy.Severalstrategiesarectmendyusedtoenhancethe ;specificityandefficiencyofthrombolvicagents,oneofthem ;isdrugtargeting,i.e.predominantthrombolyticagentsac? ;cumulatinginthetargetzoneindependentlyonthemethod ;androuteofdrugadministration.Herewefocusontheas? ;pectsofthreethrombus?-targetedthrombolytictherapy:anti?- ;bodymediatedthrombolysis,catheterdirectedfibrinolysis

    ;andnanoparticletargetedthrombolyticagents.

    ;Antibodymediatedthrombolysisisaconceptuallynew ;approachtoenhancingthespecificityandpotencyofthrom? ;bolytictherapythattargetingthethrombolvicagentsto ;thrombusbymeansofmonoclonalantibodiesthatbindt0 ;predefinedepitopesontheclot.Significantlyincreasedfib? ;rinolyticpotencyandspecificityhavebeendemonstratedin ;vitroandinvivobychemicalconjugatesofavarietyofplas? ;minogenactivatorsthmoneclonalantibodiestargettofibrin ;oractivatedplatelets.Furthermore,bispecificmoneclonal ;antibodiescontainingonesitethatrecognizesthethrombus ;epitopeandonesitebindstotheplasminogenactivatorare

    ;alsostudied.Suchduplexantibodiesareobtainedbychemi. ;calcoupling,recombinantDNAtechnologyorhybridization

    ;hybridomamethod,whichhasshowntoconcentratethem. ;InstitutemDf0gy,UniollHospital,MedicalCorSe,Huazhong ;UniversityofSc/enceand7,l.,Wuhan430022,

    ;peuticagentatthesurfaceofthethrombus.Thebispecific ;antifibrin?-antiplateletplasminogenactivatorconjugatearere?- ;portedtoachievedahigherplasminogenactivationandse? ;lectivitycomparetothatofthemonospecificconjugate.All ;thesemoleculesproducefullfibrinol~icactivi~withoutde? ;tectablefibrinogenbreakdowneitherinvitroandinvivoand ;itsplasmaclearanceratesissiginificantlowerthanitsparent ;molecular.Antibodytargetedthrombolysisshowspromiseto ;beapotentiallyvaluablethrombolyticmethodforthetreat

    ;mentofthrombosis.However,thehighimmunogenicityof ;murineantibodyandthedestructionreactionofFcfragment ;ofawholeantibobytoplateletconfinesitsclinicalpractice. ;Inaddition,itishardtoacquirelargeamount,stableand ;uniformmoneclonalantibody.Toreducetheimmunogenicity ;ofmurinemoneclonalantibodyandovercomethehuman ;againstmurineantibodyreaction(HAMA),manymethods ;arepresentedtoconstructandexpressahumanizedantibody ;withhighaffinityandspecificitytothrombusincludingcon? ;structingCDR3library,errorpronePCRandDNAshuffling

    ;program?

    ;Catheter-directedthrombolytictherapyaretestedas ;earlyas1960fortreatmentforperipheralarteryocclusion ;andformyocardialinfarction.Nowitiswidelyacceptedas ;partofclinicalpracticeforvariousthromboticdisordersin

    ;eludingmyocardialinfarction,cerebralinfarction,peripher

    ;alarteryocclusionsanddeepvenousthrombosisetc. ;Regionaltreatmentofthrombosisdoesachievebetter ;recanalizationthansystemictherapy.Ontheotherhand, ;comparedtoopensurgery,catheter-directedthrombolytic ;therapyofferthepotentialtorestorearterialpeffusionwith

    ;outtheneedforopensusgeryinmanycases.Inaddition, ;thrombolysiscanclearthrombusfromsmallarteriesthatare ;inaccessibletoaballooncatheter.t~tty,succe~fulthrom

    ;bolysismayunmaskthelesionresponsiblefortheocclusion ;

    ;andallowadirected,sometimeslessinvasivetreatment. ;However.suchtreatmentremainhas90disadvantages. ;Firstly,thrombolytictreatmentsisnotrestrictedtothere

    ;gioninquestion,hemorrhagictransformationandahigher

    ;riskofrethrombosisstillalethemajorcomplications.The ;volumestypicallydeliveredtotheregionalthempyfarexceed ;whatconldbelimitedtothelocalofinfusion.111ebio.

    ;chemicaleventsoccurringinthebloodandtheincidenceof ;asystemiclyticstatealecomparabletothosethatfollowsys

    ;temicadministration.Morever,thebleedingcomplication ;wasnotconfinedtothecatheterizationsitealone.Secondly, ;themostimportantstepforaSUCCessfullocaldeliveryisthe ;correctlodgingoftheinfusioncatheterintotheoccluded ;vesselandpenetrationintothethrow.busththeguidewire. ;rI11euseofsuchtechniquesrequireswellequipmentedlabo

    ;mtoryandwelltrainedmedicalworkev3whichisnotpopu

    ;larizationinChinacurrently.Finally,despitealloftheex

    ;pefiencewithdirectintmarterialthmmbolysis,onlyfewof

    ;theclinicaltrailsinthisfieldaleprospective,randomized ;andcontrolledstudies.Therefore,atrulythrombusspecif-

    ;ic,noninvasiveandsafethempyalestillthehottopicof ;futurethmmbolysis.

    ;Nanoparticlesmediateddrugorgenedeliverysystemis

    ;anewandevolvingmethodfortargetedthrombolysisthem

    ;PY,variouspotentialplicationsofnanoparticlesfordeliv

    ;eryoftherapeuticagentstothecellsandtissueisundergoing ;extensiveinvestigation.Nanoparticletargetedthempyused

    ;nanoparticleasthetransferringcarriertoencapsulatediffer. ;entagentsincludingplasmidDNA,proteinsandpeptides ;andlowmolecularweightcompoundsorincorporatespecific ;drugtreatmentsintothesurfaceofthenanoparticle,then ;putdifferenttargetingmoietiesonthesurfaceofthe ;nanoparticle,thenthesenanoparticlecanbelocalizedtothe ;placewherelesiontakesplacethroughthephysioehemicalor ;biologicaldirectionandexertitstherapeuticeffects. ;Nanoparticlesofbiodegradablepolymerscanprovidean ;idealcarrierfortherapeuticagentsandrealizeacontrolled ;andtargeteddeliveryofthedrugwithbetterefficacyand ;fewersideeffects.Recently,directednanopartlcletechno1. ;ogyhasbeenwidelyresearchedforthediagnosisandtreat. ;mentoftumorandinflammatorydisordersandhasachieved ;ChineseJoumalaF33tromb~isandHemostasis2OO4Vol10No3 ;muchprogress.Therecentuseofalpha(v)beta(3)targeted

    ;nanoparticlestodeliveragenetotunlorvaseulatureselec

    ;tivelyresultedinsubstantialtumorregressioninseveralex

    ;perimentalmousetumoul-models.Morever,somenovelfib

    ;rin-targetednanoparticlecontrastagentforfibrindetection ;havebeendevelopedandthesensitivityforfibdetection

    ;wasdefinedinvitroandinvivo.Thetargetedcontrastagent ;hadhighavidityforfibrinanddramaticallyimprovedthede

    ;tectabilityofclots.Theseresultssuggestthatmolecular ;imagingoffibrintargetednanoparticlescanpmvidesensitive ;detectionandlocalizationoffibrinandmayleadingtoearly ;therapeuticdecisions.Scientistshavedevelopedapolymer

    ;izednanoparticleplatformtechnologythatwillallowusto ;putdifferenttargetingmoietiesonthesurfaceoftheparticles ;inadditiontoloadingthepanicleswithdifferentcontrast ;andtherapeuticagents.UsingthiscombinedtargetediIlag

    ;ingandtherapyapproach,wealeoptimisticthattargeted ;treatmentregimenscanbedevelopedforthrombosis.With ;theincorporationofspecificdrugtrealmentsintothe ;nanopardcuLatecontrastagent,molecularlagiIlgofthrom

    ;bus-targetednanoparticlemayyieldreliabledetectionand ;quantificationofthmmbusandfacilitatetargeteddrugthem

    ;Py.Morever,usingnanoparticlestodeliverdrugscanover

    ;comethebloodbrainbalTier(BBB),slowdrugsreleasein ;thebrainanddecreaseperipheraltoxicity,so,theuseof ;nanoparticlesmayprovideasignificantadvantagetocurrent ;strategiesforcerebmvasularthrombosis.

    ;Althoughnanoparticletechnologyisaprogressive, ;rapidlyadvancingfieldinbiotechnology,however,impor. ;tanthurdlesremainbeforethenanoparficle.-targetedthrom.. ;belyrictherapy.Oneofthemajorobstaclestothetargeted ;deliveryofnanoparticleisthebody’sowndefencemecha.

    ;nismincapturingforeignparticlesbythereticuloendothelial ;system(RES).Introducinghydrophilicpolyethylenecol

    ;(PEG)tomodifypolymericnanoparficlesseemstoav0id ;theiruptakebyRES.Recentinitiativeonthedesignof ;

    ;macmmolecularhomingdevices’8eenl$todisguise

    ;nanoparticlesfromtheRES,furtherexperimentsareneeded ;toverifyitsutility.

    ;(收稿日期:20o4-03-o0)

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